The potential association between active smoking and sporadic ALS: a systematic review and meta-analysis

Abstract

Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder traditionally categorized into familial and sporadic forms. Approximately 90% of cases are classified as sporadic (sALS), and relatives of affected individuals face a 4-to-5-fold higher risk of developing the disease. While mutations in genes such as SOD1, C9orf72, and TARDBP are established drivers, both genetic susceptibility and environmental exposures contribute to disease onset and progression. Tobacco smoke is a leading environmental candidate, potentially driving pathogenesis via chronic inflammation, heavy-metal neurotoxicity, and oxidative stress. However, the epidemiological strength of the association between smoking and sALS remains a subject of ongoing debate. Objective: To conduct a systematic review and meta-analysis on the relationship between active tobacco smoking and the risk of sALS development. Methods: This systematic review and meta-analysis followed Cochrane and PRISMA 2020 guidelines. We searched for all studies published until July 5th, 2025 in Scopus, PubMed/MEDLINE, Web of Science and BVS that associated tobacco smoking and sALS. Data were pooled using a random-effects model using the Inverse Variance method and the Restricted Maximum Likelihood estimator, with a 95% Confidence Interval (CI). Funnel Plots with enhanced contour and Egger’s test were used to address publication bias. Risk of bias was evaluated using Newcastle Ottawa Scale. (PROSPERO: #CRD42025603657). Results: Twelve studies were included, comprising 8 case-control studies and 4 Mendelian Randomization (MR) studies. The pooled analysis of case-control studies showed no clear association (OR 1.03; 95% CI 0.78 to 1.37; p = 0.819). A sensitivity analysis using the leave-one-out method demonstrated that the pooled case-control results were robust, and no evidence of publication bias was found (Egger’s Test p=0.391). On the other side, MR studies searched whether a genetic variant that demonstrably increases the propensity to smoke is also associated with a higher (or lower) risk of ALS. MR results were divergent: two 2019 studies reported a positive genetic correlation (OR 1.25, 95% CI 1.01–1.55; and regression coefficient 0.42, p<0.002). Conversely, a 2020 MR found no causal relationship (p>0.05). A 2025 MR also showed no significant association across smoking phenotypes, though a potential protective effect of smoking cessation was noted (OR 0.830, p<0.001), but only in the IVW model. The discrepancy between early positive MR results and the consistently neutral findings of pooled case-control data suggests that previous associations may have been influenced by confounding or limited SNP selection. Conclusion: Current evidence does not support association between smoking and sALS, and there are inconsistencies with MR study results. Further prospective cohort studies are encouraged to clarify whether smoking represents a modifiable risk factor for sALS.